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1. Hedonic eating, obesity, and addiction result from increased neuropeptide Y in the nucleus accumbens during human brain evolution

   https://doi.org/10.1073/pnas.2311118120  

   Raghanti, Mary Ann ; Miller, Elaine N. ; Jones, Danielle N. ; Smith, Heather N. ; Munger, Emily L. ; Edler, Melissa K. ; Phillips, Kimberley A. ; Hopkins, William D. ; Hof, Patrick R. ; Sherwood, Chet C. ; et al ( September 2023 , Proceedings of the National Academy of Sciences)

   The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.

    

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2. A comparison of cannabinoid receptor 1-immunoreactive axon density in the amygdala among nine primate species

   Jones, DN ( January 2022 , Abstracts Society for Neuroscience)

   The amygdala is a sensory integration center that plays an important role in emotional learning, behavior, and motivation. Cannabinoid signaling in the amygdala modulates aspects of anxiety, aggression, and fear in rodents via cannabinoid receptor 1, however little is known about cannabinoid signaling in the amygdala of humans and nonhuman primates. Primates are behaviorally diverse, with closely related species often displaying distinct social styles characterized by varying degrees of social tolerance and agonistic tendencies. Such behavioral differences are thought to be associated with neurochemical differences among species. Given what is known about the functional role of cannabinoid signaling in the amygdala, we tested whether relatively tolerant species, such as humans, bonobos, and marmosets, possess relatively higher cannabinoid receptor 1-immunoreactive (CB1R-ir) axon density in the basolateral amygdala. We used immunohistochemistry and stereological methods to compare CB1R-ir axon density among 47 primates representing nine species: humans (n=5), chimpanzees (n=6), bonobos (n=2), baboons (n=6), rhesus macaques (n=5), Japanese macaques (n=6), pigtail macaques (n=6), marmosets (n=5), and capuchins (n=6). The basolateral amygdala is comprised of the lateral, basal, and accessory basal nuclei. Stereological data for each nucleus was collected separately. After ruling out sex differences within each species, we used repeated measures ANOVA to evaluate species differences. The interaction (F16,76 = 5.061, p<.001) and main effects of species (F8,38 = 8.007, p<.001) and area (F2,76 = 59.616, p<.001) were all significant. However, the observedspecies differences did not support our hypothesis related to social tolerance nor did the data conform to a phylogenetic pattern. Instead, we found that while some closely related species differed from each other in a nucleus-dependent manner, some distantly related species shared unexpected similarities. Our results highlight the need for additional comparative work on the cannabinoid system from a molecular and genetic perspective. We discuss the implications of our observations with special focus on primate brain evolution and its connection to primate social style. 

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3. Toward a predictive model of serotonergic densities: A supercomputing simulation of reflected fractional Brownian motion in a 3D-mouse brain shape

   Janusonis, Skirmantas ; Haiman, Justin H. ; Metzler, Ralf ; Vojta, Thomas ( July 2023 , Organization for Computational Neurosciences (OCNS))

   In vertebrate brains, virtually all neural circuits operate inside a dense matrix of axons (fibers) that have a strongly stochastic character. These fibers originate in the brainstem raphe region, produce highly tortuous trajectories, and release serotonin (5-hydroxytryptamine, 5-HT), with other neurotransmitters. They can robustly regenerate in the adult mammalian brain and appear to support neuroplasticity [1], with implications for mental disorders [2] and artificial neural networks [3]. The self-organization of this “serotonergic” matrix remains poorly understood. In our previous study, we have shown that serotonergic fibers can be modeled as paths of fractional Brownian motion (FBM), a continuous-time stochastic process. FBM is parametrized by the Hurst index, which defines three distinctive regimes: subdiffusion (H < 0.5), normal diffusion (H = 0.5), and superdiffusion (H > 0.5). In two-dimensional (2D) shapes based on the adult mouse brain, simulated FBM-fibers (with H = 0.8) have produced regional distributions similar to those of the actual serotonergic fibers [4]. However, increments of superdiffusive FBM trajectories have long-range positive correlations, which implies that a fiber path in one 2D-section depends on its history in other sections. In a major extension of this study, we used a supercomputing simulation to generate 960 fibers in a complex, three-dimensional shape based on the late-embryonic mouse brain (at embryonic day 17.5). The fibers were modeled as paths of reflected FBM with H = 0.8. The reflection was caused by natural neuroanatomical borders such as the pia and ventricles. The resultant regional densities were compared to the actual fiber densities in the corresponding neuroanatomically-defined regions, based on a recently published comprehensive map [5]. The relative simulated densities showed strong similarities to the actual densities in the telencephalon, diencephalon, and mesencephalon. The current simulation does not include tissue heterogeneities, but it can be further improved with novel models of multifractional FBM, such as the one introduced by our group [6]. The study demonstrates that serotonergic fiber densities can be strongly influenced by the geometry of the brain, with implications for neurodevelopment, neuroplasticity, and brain evolution. Acknowledgements: This research was funded by an NSF-BMBF CRCNS grant (NSF #2112862 to SJ & TV; BMBF #STAXS to RM). References: 1. Lesch KP, Waider J. Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron. 2012, 76, 175-191. 2. Daws RE, Timmermann C, Giribaldi B, et al. Increased global integration in the brain after psilocybin therapy for depression. Nat. Med. 2022, 28, 844-851. 3. Lee C, Zhang Z, Janušonis S. Brain serotonergic fibers suggest anomalous diffusion-based dropout in artificial neural networks. Front. Neurosci. 2022, 16, 949934. 4. Janušonis S, Detering N, Metzler R, Vojta T. Serotonergic axons as fractional Brownian motion paths: Insights Into the self-organization of regional densities. Front. Comput. Neurosci. 2020, 14, 56. 5. Awasthi JR, Tamada K, Overton ETN, Takumi T. Comprehensive topographical map of the serotonergic fibers in the male mouse brain. J. Comp. Neurol. 2021, 529, 1391-1429. 6. Wang W, Balcerek M, Burnecki K, et al. Memory-multi-fractional Brownian motion with continuous correlation. arXiv. 2023, 2303.01551. 

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4. Reflected Fractional Brownian Motion in 3D-Brain Shapes: Insights into the Distribution of Serotonergic Axons

   Janusonis, Skirmantas ; Metzler, Ralf ; Vojta, Thomas ( January 2022 , Organization for Computational Neurosciences (OCNS))

   The immediate neighborhood of virtually every brain neuron contains thin, meandering axons that release serotonin (5-HT). These axons, also referred to as serotonergic fibers, are present in nearly all studied nervous systems (both vertebrate and invertebrate) and appear to be a key component of biological neural networks. In the mammalian brain, they create dense meshworks that are macroscopically described by densities. It is not known how these densities arise from the trajectories of individual fibers, each of which resembles a unique random-walk path. This poses interesting theoretical questions, solving which will advance our understanding of brain plasticity and regeneration. For example, serotonin-associated psychedelics have recently been shown to promote global brain integration in depression [1], and serotonergic fibers are nearly unique in their ability to robustly regenerate in the adult mammalian brain [2]. We have recently introduced a conceptual framework that treats the serotonergic axons as “stochastic axons.” Stochastic axons are different from axons that support point-to-point connectivity (often studied with graph-theoretical methods) and require novel theoretical approaches. We have shown that serotonergic axons can be potentially modeled as paths of fractional Brownian motion (FBM) in the superdiffusive regime (with the Hurst exponent H > 0.5). Our supercomputing simulations demonstrate that particles driven by reflected FBM (rFBM) accumulate at the border enclosing the shape [3]. Likewise, serotonergic fibers tend to accumulate at the border of neural tissue, in addition to their general similarity to simulated FBM paths [4]. This work expands our previous simulations in 2D-brain-like shapes by considering the full 3D-geometry of the brain. This transition is not trivial and cannot be reduced to independent 2D-sections because increments of FBM trajectories exhibit long-range correlation. Supercomputing simulations of rFMB (H > 0.5) were performed in the reconstructed 3D-geometry of a mouse brain at embryonic day 17 (serotonergic fibers are already well developed at this age and begin to invade the cortical plate). The obtained results were compared to the actual distribution of fibers in the mouse brain. In addition, we obtained preliminary results by simulating rFBM with a region-dependent H. This next step in complexity presents challenges (e.g., it can be highly sensitive to mathematical specifications), but it is necessary for the predictive modeling of interior fiber densities in heterogenous brain tissue. 

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5. Japanese and rhesus macaques differ in amygdala cannabinoid 1 receptor-immunoreactive axon density (P078.09)

   Jones, D.N. ; Smith, HN ; Hirter, KN ; Munger, EL ; Hof, PR ; Sherwood, CC ; Raghanti, MA ( October 2021 , Abstracts Society for Neuroscience)

   Endogenous and exogenous cannabinoids signal through the cannabinoid 1 receptor (CB1R) to modulate various aspects of social behavior, including aggression and anxiety. In rodents and primates, CB1R expression in the basolateral amygdala is dense and cannabinoid signaling in this region has been reported to influence social behavior. Little is known about how endocannabinoid signaling in the amygdala contributes to primate social diversity. The behaviorally diverse and species-rich cercopithecoid monkey genus Macaca is an ideal model for addressing this topic. Japanese (Macaca fuscata) and rhesus macaques (M. mulatta) display similar social styles in some respects; however, there is evidence to suggest they differ in their stress response, amygdala structure, and monoaminergic signaling. To further assess the molecular basis of social style in Japanese and rhesus macaques, we used immunohistochemistry and stereological methods to compare CB1R-immunoreactive (CB1R-ir) axon density in the basolateral amygdala, which is comprised of the lateral, basal, and accessory basal nuclei. Our study sample included 6 Japanese and 5 rhesus macaques. Repeated-measures ANOVAs were used to evaluate species differences, with amygdala region as the within-subjects measure and species as the between-subjects factor. This revealed significant main effects for species and area (p values < 0.05) with no interaction. Post hoc tests revealed higher CB1R-ir axon density in the basal and accessory basal nuclei of rhesus macaques compared to Japanese macaques. Our results suggest that CB1R-mediated signaling in the lateral nucleus of the amygdala is comparable between the two species, while the differences we observed in the basal and accessory basal nuclei may contribute to the nuanced behavioral differences observed between them. 

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